Masayuki Shirasawa1, Tatsuya Yoshida2, Yukiko Shimoda1, Daisuke Takayanagi3, Kouya Shiraishi3, Takashi Kubo4, Sachiyo Mitani4, Yuji Matsumoto1, Ken Masuda1, Yuki Shinno1, Yusuke Okuma1, Yasushi Goto1, Hidehito Horinouchi1, Hitoshi Ichikawa4, Takashi Kohno3, Noboru Yamamoto5, Shingo Matsumoto6, Koichi Goto6, Shun-Ichi Watanabe7, Yuichiro Ohe1, Noriko Motoi8. 1. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. 2. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. Electronic address: tatyoshi@ncc.go.jp. 3. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. 4. Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan. 5. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. 6. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. 7. Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan. 8. Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
Abstract
INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression. METHODS: We retrospectively reviewed patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti-PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing. RESULTS: Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1High (tumor proportion score ≥ 50%)/TILHigh (≥85/mm2; n = 73); type II: PD-L1Low (tumor proportion score < 50%)/TILLow (<85/mm2; n = 70); type III: PD-L1High/TILLow (n = 37); and type IV: PD-L1Low/TILHigh (n = 48). The objective response rate (ORR) and progression-free survival (PFS) of anti-PD-1/PD-L1 therapy clearly differed according to the different TME types (ORR and PFS; type I: 64%, 14.5 mo; type II: 12%, 2.1 mo; type III: 24%, 3.6 mo; type IV; 41%, 10.8 mo). In patients with PD-L1High tumors, type I tumors had significantly better ORR and PFS than type III tumors (ORR: p < 0.001 and PFS: p < 0.001). The presence of TP53 and KRAS mutation was related to the density of CD8-positive TILs and PD-L1 expression, respectively. CONCLUSIONS: Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti-PD-1/PD-L1 therapy.
INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression. METHODS: We retrospectively reviewed patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti-PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing. RESULTS: Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1High (tumor proportion score ≥ 50%)/TILHigh (≥85/mm2; n = 73); type II: PD-L1Low (tumor proportion score < 50%)/TILLow (<85/mm2; n = 70); type III: PD-L1High/TILLow (n = 37); and type IV: PD-L1Low/TILHigh (n = 48). The objective response rate (ORR) and progression-free survival (PFS) of anti-PD-1/PD-L1 therapy clearly differed according to the different TME types (ORR and PFS; type I: 64%, 14.5 mo; type II: 12%, 2.1 mo; type III: 24%, 3.6 mo; type IV; 41%, 10.8 mo). In patients with PD-L1High tumors, type I tumors had significantly better ORR and PFS than type III tumors (ORR: p < 0.001 and PFS: p < 0.001). The presence of TP53 and KRAS mutation was related to the density of CD8-positive TILs and PD-L1 expression, respectively. CONCLUSIONS: Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti-PD-1/PD-L1 therapy.